Relevance of Fc-effector functions for prevention of infection of the first cell in the HIV nonhuman primate model

• Applicants: Dr. Christiane Stahl-Hennig; Professor Dr. Klaus Überla
• Subject Area: Virology
• Term: from 2012 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 210650650

The recent development of potent, broadly-neutralizing antibodies against HIV-1 has fueled interest in passive immunization strategies to prevent, treat, and eradicate HIV infection. Non-human primate studies have shown, that neutralizing antibodies can prevent systemic infection as defined by detectable levels of viral RNA in the blood and seroconversion. However, this does not reveal whether the virus replicates in the exposed mucosa or draining lymph nodes before it is contained. If this were the case, latently infected cells are generated, that may reactive virus when antibody concentrations have fallen beyond protective levels. Detection of infectious virus at distal sites early after mucosal exposure in the presence of a neutralizing antibody protecting from systemic infection has raised doubts whether neutralizing antibodies can prevent infection of the first cell by HIV at all and thus provide sterilizing immunity in the strictest sense. During the previous funding period, we have therefore developed a novel challenge virus, that uses HIV-1 Env for entry during the first infection cycle, but then switches to SIV Env for all subsequent rounds. Since SIV Env is not recognized by the HIV Env antibody used in our study, protection mediated by this HIV antibody must be due to blocking infection of the first cell. Using a conventional low-dose and a novel simultaneous high-dose rectal challenge in non-human primates, we observed protection from infection with the novel challenge virus. To the best of our knowledge, this is the first direct evidence that antibodies can provide sterilizing immunity in the strictest sense after mucosal exposure to any virus. The simultaneous high dose challenge, which also allowed to quantify how efficiently infection of the first cell is blocked, revealed that the HIV antibody reduced the number of infection events of the first cell more than 60-fold. After natural low-dose exposure in humans, such a reduction in the number of first infection events should greatly reduce the probability of infection and thus provide sterilizing immunity against HIV-1. We also observed a 4.6-fold reduction of first infection events under conditions, in which the HIV antibody bound to the virion without neutralizing it. Since blocking infection of the first cell should be the best way of protection and since effector mechanisms providing sterilizing immunity in the strictest sense may differ from those required for control of virus replication at subsequent steps a better understanding of mechanisms blocking infection of the first cell, is needed. For the next funding period we therefore propose to determine the relevance of Fc-effector functions for prevention of infection of the first cell by neutralization and non-neutralizing mechanisms. In addition, the influence of the extent of opsonisation of the incoming virion for preventing infection of the first cell will be explored.

• DFG Programme: Research Grants